John Spinelli

Professor

Relevant Degree Programs

 

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
Occupational exposure to polycyclic aromatic hydrocarbons, breast cancer risk, and interactions with genetic variants (2017)

Polycyclic aromatic hydrocarbons (PAHs) are created by the incomplete combustion of fossil fuels, and are established human carcinogens. However, the effect of occupational PAH exposure on breast cancer is not well established. In addition, it is not known if genes involved in metabolizing xenobiotic compounds modify the risk of breast cancer in women exposed to PAHs. The objectives of this study were to (1) estimate the association between PAH exposure and breast cancer, (2) examine how variants of select xenobiotic metabolizing genes influence breast cancer risk, and (3) assess how these variants – several of which are involved in PAH metabolism – interact with PAH exposure to modify breast cancer risk. The relationships between PAH exposure, genetic susceptibility, and breast cancer were examined in a population-based case control study conducted in Vancouver, BC and Kingston, Ontario. A detailed questionnaire, including occupational history, and biological sample were collected from participants. Chapter 2 details how I developed a statistical model that predicts the probability of exceeding the permissible exposure limit for PAH through industry and occupation using workplace compliance testing data collected in the United States. Chapter 3 describes the use of the model to develop a job exposure matrix and estimate the association between PAH exposure and breast cancer. In Chapter 4, I assessed the associations between select gene variants and breast cancer, and evaluated whether there is evidence that those variants modify PAH exposure effect on breast cancer risk. Long term exposure to PAHs was identified as a risk factor for breast cancer, and risk was highest among premenopausal women and women with a first degree family history of breast cancer. Six variants in xenobiotic metabolizing genes were observed to be related to breast cancer risk, three of which are directly involved in PAH metabolism. In addition, there is evidence to support the notion that three of these variants modify the effect of PAH exposure, implicating the role gene-environment interactions have on modifying breast cancer risk. Evidence from this research points to the potential importance of monitoring and limiting occupational exposures to PAHs in order to reduce breast cancer risk in women.

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Late effects among young adult cancer survivors (2014)

Background and objective: Long term young adult cancer survivors (YACS) can face serious life-threatening complications in multiple organ systems, and these may become more clinically significant with aging. However, there have been limited attempts to understand the risk of late-effects in this group. Therefore, this thesis aimed: to measure the overall and cause-specific risks of late effects among YACS, including late mortality, SMN and late morbidity leading to hospitalization; to identify the characteristics influence these risks; and to examine YACS’ willingness in participating late effects studies in the future. Methods: The first three studies used data collected from Childhood Adolescent and Young Adult Cancer Survivor (CAYACS) research program, an ongoing retrospective cohort study. In the fourth study, YACS were surveyed regarding their willingness to participate in late effects studies in the future. Cox proportional hazard regression and multivariate logistic regression models were used to examine the relationship between outcomes (late effects and willingness of participation) and key socio-demographic, clinical-related factors, including the primary cancer diagnosis. Results: YACS showed increased risks of mortality, SMN and late morbidity leading to hospitalization compared with the general population. The diagnosis of the primary cancer had a significant impact on survivors’ mortality and SMN. The highest risk of mortality was observed among central nervous system (CNS) tumor survivors, whereas the highest risk of SMN were seen in survivors of lymphoma. The risk of late morbidity were higher among survivors receiving all three treatment modalities, including chemotherapy, RT and surgery. The survey study found that a large majority of the respondents were always willing to participate future genetic studies. Study methods, study sponsorship, and health concerns affected subjects’ willingness to some degree. Ethnicity and income were independently associated with willingness to participate.Conclusion: This research identifies the late effects among YACS and the feasibility of conducting late effects studies in the future. Evidence from this work points to the importance of careful monitoring for these late health problems which could reduce the overall late effects and to the need to develop effective clinical programs and guidelines to meet the needs of this population.

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Master's Student Supervision (2010 - 2018)
Interactions between cytochrome P450 genetic polymorphisms and plasma organochlorines in non-Hodgkin lymphoma (2014)

Following World War II, the production of chlorine-containing organic molecules known as organochlorines (OCs) became commonplace. Although heightened regulation has since occurred in Canada, OCs continue to pose health and environmental concerns due to their persistence and ongoing use elsewhere.To date, the largest study assessing the association between plasma OCs and non-Hodgkin lymphoma (NHL) was conducted in British Columbia (BC) between 2000 and 2004. Eight hundred twenty-eight newly diagnosed NHL cases were ascertained from the BC Cancer Registry and 848 population controls were randomly obtained from the BC Ministry of Health Client Registry. Significant associations were observed between NHL and 14 individual organochlorines.Because the effects of OCs on NHL may be modified by an individual’s genetic makeup, gene-environment (GxE) interactions between OCs and cytochrome P450 (CYP) genes were examined here, using data from the subset of participants of European ethnic origin (“Europeans”) in the BC study. CYPs were chosen because they are involved in the metabolism of chemicals, including some OCs.First, the effects of the OCs were re-evaluated in Europeans only, as this was the analytic group in subsequent genetic analyses. Significant trends were noted for polychlorinated biphenyls (PCBs) 153, 180, 187, summed PCBs (total, dioxin-like, non-dioxin-like), beta-hexachlorocyclohexane (β-HCCH), hexachlorobenzene (HCB), mirex, trans-nonachlor, and oxychlordane. Significance was maintained after controlling for multiple testing for PCB-187, total summed PCBs, β-HCCH, HCB, trans-nonachlor, and oxychlordane. No significant trends were found for PCB-28, 99, 105, 118, 138, 156, 170, 183, cis-nonachlor, p, p’-DDT, or p, p’-DDE.Secondly, 129 single nucleotide polymorphisms (SNPs) in 18 CYP genes were selected for study. Significant trends were noted for rs743572 (CYP17A1) and rs1322179 (CYP2C19). Significance was not maintained after controlling for multiple testing. Two SNPs, rs9332197 and rs10509679 (CYP2C9), in the same gene cluster as CYP2C19 were of borderline non-significance.A significant GxE interaction was found between rs743572 and mirex, even after controlling for multiple testing. The increased risk of NHL conferred by higher mirex levels is lessened in minor allele homozygotes of rs743572. As CYP17A1 is involved in steroid metabolism, these results suggest the involvement of hormonal modulation in NHL risk.

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Mortality among British Columbians testing for hepatitis C antibody, 1992-2004 (2011)

Background: Hepatitis C virus (HCV) infection is a major preventable and treatable cause of morbidity and mortality. The ability to link records between population-based centralized laboratory HCV testing data and administrative databases has provided a unique opportunity to compare mortality and morbidity between HCV seronegative and seropositive individuals. Through the use of laboratory testing patterns and results, this study attempts to differentiate the viral effects of mortality due to HCV infection from risk behaviours/activities that are associated with acquisition of HCV infection.Methods: Serological testing data at the British Columbia (BC) Centre for Disease Control from 1992-2004 were linked to the death registry at the BC Vital Statistics Agency. Four groups of HCV testers were defined by their HCV antibody (anti-HCV) testing patterns: single non-reactive (SNR); serial multiple tested non-reactive (MNR); reactive at initial testing (REAC); and seroconverter (previously seronegative followed by reactive, a marker for incident infection) (SERO). Standardized mortality ratios were generated to compare all-cause and disease specific mortality with the BC population. Time-dependent Cox proportional hazard regression was used to compare hazard ratios among HCV serological groups.Results: Anti-HCV testers were found to have higher mortality than the BC population. Referent to the SNR group, the REAC group had higher risks for liver-related mortality (hazard ratio (HR): 9.71, 95% confidence interval (CI): 8.62-10.87) and drug-related mortality (HR: 13.51, 95% CI: 11.63-15.63). When compared to the REAC group, the SERO group had a lower risk for liver-related mortality (HR: 0.53, 95% CI: 0.24-0.92), but a higher risk for drug-related mortality (HR: 1.60, 95% CI: 1.20-2.08).Conclusions: These findings confirm that anti-HCV positive testers have increased mortality due to chronic infection related to progressive liver disease, and that a substantial proportion of the mortality is attributable to drug use and risk behaviours/activities associated with HCV acquisition. Mortality reduction in HCV infected individuals will require comprehensive prevention programming to reduce the impact of mental health and problematic substance use behaviours/activities which relate to HCV acquisition, as well as HCV treatment to prevent progression of chronic liver disease.

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